Abstract Health problems caused by sleep disruption and/or insufficiency have been recognized and documented in a report from the Institute of Medicine in 2006. This has emerged, to a large extent, from the pervasive social- networking and rapid information exchange world that came upon us in recent decades. The increasing usage of electro-digital devices after dusk negatively affects sleep quality and quantity. In addition, the need for shift- work schedule to suit the 24/7 society and for the frequent transmeridian travels have both increased dramatically in the last few decades. Hence, sleep deprivation and disruption have become inevitable for many people in the societies that we live. Concurrently, our world is facing a greater challenge in maintaining our brain healthy. Poor sleep has been suggested to contribute to dementia such as Alzheimer's Disease. Recently, we have found a mutation from humans whose sleep need is less than the general population. This mutation, when engineered into mice, also enables these mice to sleep less than control mice. These results imply that mouse is an excellent model for studying relevant molecular mechanisms. We also have established many useful reagents and mouse models in the last several years and are now in a position where we can apply these resources and methodologies to investigate these mechanisms. Currently, the theories of the functions of sleep include energy regeneration and allocation, synaptic plasticity maintenance, and neurotoxin clearance, etc. One of the most intriguing questions that arise from observing the natural short sleepers who we have been studying for a long time is that they don't seem to have negative health consequence (cognitively and physically) from life-long sleeping less. We hypothesize that the natural short sleeper mutation somehow endows the brains of these human subjects the ability to perform whatever necessary functions occur during sleep in a much more efficient manner and can complete these daily tasks in a shorter period even though these people stay awake longer than regular people each day. Alternatively, the brains of these natural short sleepers may not accumulate as much waste products during wakefulness as the regular sleepers. These possibilities are not mutually exclusive. Here we propose to investigate these possibilities with our mouse models. We will investigate whether the mice carrying this human short sleep mutation can execute neurotoxin clearance more efficiently and/or accumulate less neurotoxin than control mice. We will determine the specific cell types that are participating in DEC2's (the short sleep gene) function in the brain. We will also investigate the inter-relationship between DEC2 and Hypocretin, which plays a critical role in sleep-wake maintenance and A? clearance. We have outlined three independent yet complementary aims in this grant. The results of these studies will pave the way for future investigations of mechanisms/networks that interact to regulate healthy brain functions during sleep. The outcome of these studies will provide novel opportunities for therapeutic intervention of sleep-related disorders and innovative aids for recovery functions of sleep.